The goal of this project is the clinical alleviation of human disease caused by sickle cell hemoglobin (HB S). The disease manifests itself in erythrocyte sickling resulting from the polymerization of deoxy-Hb S molecules into fibrous structures. When the interactions of Hb S molecules leading to polymerization are known, prevention of sickling can be attempted in a specific and systematic fashion, rather than by empirical approaches. The broad objectives are thus to determine the sites on the aberrant hemoglobin molecule that are responsible for the intermolecular interactions and subsequently, from this knowledge, to design an interactant that may combine with one or more of the sites through polar, non-polar, van der Waals forces, hydrogen bonding, or salt linkages to prevent aggregation. This substance must satisfy the conditions that it does not interfere with hemoglobin function, and is not toxic. X-ray diffraction and computer model building are being used to determine the details of the sites involved in deoxy-Hb S interactions. It has been shown from our X-ray diffraction data and electron microscopy that the deoxy-Hb S molecules form stacked hexagonal discs, each rotated with respect to the other by an azimuthal angle of about 7.3 degrees. Comparison of diffraction data with Bessel Fourier transforms of the deoxy-Hb S molecule, in which its orientation within the microtubule structure is systematically varied, should yield the requisite knowledge of intermolecular contact regions and their conformation, and would indicate modifications that may prevent sickling.